3-ethylene mercaptoles of 11-oxygenated derivatives of 17, 21-dihydroxy-4-pregnene-3, 20-diones



United States 3-ETHYLENE MERCAPTOLES OF II-OXYGEN- ATED DERIVATIVES OF17,21-DIHYDROXY- 4-PREGNENE-3,20-DIONES Jack W. Ralls, Morton Grove,11]., assignor, by mesne assignments, to G. D. Searle & Co., Skokie,111., a corporation of Delaware No Drawing. Application January 13o,1955, Serial No. 481,687

7 Claims. (Cl. 260-2395) CHr-S wherein X is a member of the classconsisting of carbonyl and carbinol radicals, and R is a member of theclass consisting of hydrogen, benzoyl and lower alkanoyl radicals suchas formyl, acetyl, propionyl, butyryl, valeryl, caproyl,cyclohexaneacetyl, cycl'opentanepropionyl, and the like.

The ease of formation and chemical stability of mercaptoles makes thesecompounds attractive intermediates in multi-stage syntheses. The studiesof Hauptmann (Jour. Amer. Chem. Soc'., vol. 69, 562; 1947) and of Ruffand Reichstein (Helvetica Chimica Acta, vol. 34, 70; 1951) on thereaction of steroid ketones with ethanedithiol have demonstrated thatthis dimercaptan group will condense with carbonyl functions at the 3-,7-, 12-, 17-, and 20-positions; the hindered 11-position is the onlysite of unreactivity. This situation has been used to advantage in theselective formation'of 7-mercaptoles from 7,11-diones and lZ-mercaptolesfrom 11,12-diones. A higher order of selectivity is required when thecompetitive reaction is between the 3- and 20-positions. I have foundthat the 3-keto group reacts under very mild conditions, for instanceacetic acid as a solvent and ptoluenesulfonic acid at a catalyst. Underthese conditions, reaction can be made to take place at the 3- positionin preference to the 11- and 20-position.

The compounds of this invention are valuable intermediates in thesynthesis of ketosteroids. Formation of these monomercaptoles protectsthe 3 keto group while other keto groups undergo chemical conversions.After such chemical conversions, the 3-ethylene mercaptole group isconveniently reconvened to a 3-ke't'o group by treatment with mercuricchloride and cadmium carbonate in aqueous acetone. However, the utilityof these compounds is not limited to their use as intermediates inorganic synthesis. The mercaptoles of this invention have unusualpharmaceutical properties. Thus, they are active lympholytic agents butlack many of the other effects of cortisone. In addition, they inhibitthe luteoid effects of progesterone.

The following examples illustrate in further detail some atent O2,744,108 Patented May 1, 1956 of the compounds which constitute theinvention and methods for their synthesis. However, the invention is notto be construed as limited in spirit or in scope by the details setforth therein. It will be apparent to those skilled in the art thatnumerous modifications in materials and in methods can be adoptedwithout departing from the invention in spirit or in scope. In theseexamples, quantities of materials are indicated in parts by weight.

This application is a continuation-in-part of my copending application,Serial No. 425,023, filed April 22, 1954.

Example 1 To a solution of 12.06 parts of cortisone acetate in 263 partsof warm acetic acid are added 2.46 parts of ethanedithiol and a solutionof 2.7 parts of p-toIuene-sulfonic acid monohydrate in 32 parts ofacetic acid. The mixture is maintained at room temperature for 15 hoursafter which the solid precipitate is collected on a filter andrecrystallized from acetone to yield l7hydroxy-21'-acetoxy-4-pregnene-3,11,20-trione 3 ethylene mercaptole melting at about256-258 C. An 0.5% chloroform solution shows a specific rotation of+210". The infrared absorption spectrum as determined in a potassiumbromide disc shows maxima at about 2.96, 5.74, 5.82, 5.95, 7.30, 7.91,8.0, and 9.52 microns.

Substitution of an equivalent amount of the cyclopentylpropionate for"the acetate of cortisone in the foregoing procedure yields thel7-hydroxy-2l-(cyclopentylpropionoxy)-4-pregnene-3,1.1,20-trione3-ethylene mercaptole.

Example 2 To a solution of 4.4 parts of 17-hydroxy-21-acetoxy-4-pregnene-3,l1,20-trione 3-ethylene mercaptole in 750 parts ofmethanol, there are added in the course of 15 minutes 88 parts of 0.5-Nmethanolic potassium bicarbonate solution with shaking. The reactionmixture is permitted to stand at room temperature for 16 hours and thenacidified with dilute acetic acid and concentrated under vacuum. Oncooling, 17,21-dihydroxy-4-pregnene- 3,11,20-trione 3-ethylenemercaptole is obtained which, recrystallized from a mixture of acetoneand petroleum ether, melts at about 210213 C. The infrared absorptionspectrum shows maxima at 2.96, 5.88, and 9.52 microns.

The identical compound is obtained by the treatment of cortisone withethanedithiol and p-toluene-sulfonic acid by the foregoing procedure.

Example 3 I OH 0 j on 0 Hrs O Hz-S The infrared absorption spectrumshows maxirna at 2.95, 5.88, 7.92, 8.92, 9.52, and 13.85 microns.

Example 4 A mixture of 100 parts of 17-hydroxycorticosterone acetate,20.2 parts of ethanedithbl, 16.7 parts of p-toluenesulfonic acidmonohydrate and 1750 parts of acetic acid is maintained at 10 C. for 12hours, after which the precipitate is collected on a filter andrecrystallized from acetone. The 115,17 dihydroxy 21 acetoxy 4-pregnene-3,20-dione 3-ethylene mercaptole thus obtained melts at about2l4-217 C.

Example 5 To a solution of 100 parts of 11,8,17-dihydroxy-2lacetoxy-4-pregnene-3,ZO-dione 3-ethylene mercaptole in4000 parts of 95% methanol there is added over a period of 15 minutesone equivalent of an 0.1-N solution of sodium hydroxide in methanol withshaking. The reaction mixture is permitted to stand at room temperaturefor 30 minutes and then concentrated under vacuum and cooled. Theprecipitated 1l 9,17,21-trihydroxy-4-pregnone-3,20-clione 3-ethylenemercaptole is collected on a filter. Further purification can beachieved by chromatography on a silica column. The compound has thestructural formula CHzOH GH -S CHaS The infrared absorption spectrumshows maxima at 2.96, 5.86, and 9.52 microns.

The identical compound is obtained by treatment of hydrocortisone withethanedithiol and p-toluenesulfonic acid by the procedure of thepreceding example.

What is claimed is:

1. A compound of the structural formula CH2OR wherein R is a member ofthe class consisting of hydrogen, lower alkanoyl and benzoyl radicalsand X is a member of the class consisting of carbonyl and carbinolradicals.

2. A compound of the structural formula CHzOH CHr-S 3. A compound of thestructural formula OHIO-C O-(lower alkyl) 0 1 -OH 0- 3 CH A, CHz-S l k0112-5 4. A compound of the structural formula CHr-S 7. A compound ofthe structural formula References Cited in the file of this patentUNITED STATES PATENTS 2,352,568 Reichstein June 27, 1944 OTHERREFERENCES Antomucci: J. Org. Chem., October 1952, pp. 1341-51.

Bernstein July 2l, 1953

1. A COMPOUND OF THE STRUCTURAL FORMULA